The McCune-Albright syndrome (MAS) is a genetic disorder characterized by constitutive activation of the Gαs proteins involved in the adenylyl cyclase enzyme. The disease is now known to be caused by a genetic mutation, commonly a substitution of histadine or cysteine for arginine at amino acid 201 in the Gαs protein. Adenylyl cyclase, with its formation of cyclic AMP (cAMP), works as a second messenger for many cellular and hormonal events. Clinically, MAS is characterized classically by precocious puberty, café-au-lait skin markings, and bone lesions termed polyostotic fibrous dysplasia. Other conditions that represent overactivity of receptor-coupled adenylate cyclase include hyperthyroidism resulting from activation of the TSH receptor, hypercortisolism (CRH and ACTH receptor activation), acromegaly (GHRH receptor activation), among others. Clinical heterozygosity of affected individuals is explained by mosaicism of the mutation.